Proteomic organ-specific ageing signatures and 20-year risk of age-related diseases: the Whitehall II observational cohort study.
Level 3 - non-randomized controlled study
Prospective observational cohort study with 20-year follow-up
PubMed 40015764 · doi:10.1016/j.landig.2025.01.006
What was done
Plasma samples were collected from 6,235 middle-aged participants (aged 45–69 years) in the Whitehall II prospective cohort study in London, UK, in 1997–1999. Proteomic profiles measured via SomaScan were used to determine biological age gaps for nine organs using the Python package organage. Participants were tracked for a mean follow-up of 19.8 years (SD 3.6; 123,712 person-years) through linkage to national health records to evaluate incident risk for 45 age-related diseases and multimorbidity. Analyses excluded baseline disease cases and adjusted for age, sex, ethnicity, and age gaps of other organs.
What was found
Larger organ age gaps were associated with an increased risk of 30 diseases. Six diseases were exclusively linked to accelerated ageing of their corresponding organ (hazard ratio [HR] per SD increment): liver failure (HR 2.13, 95% CI 1.41–3.22), dilated cardiomyopathy (HR 1.65, 95% CI 1.28–2.12), chronic heart failure (HR 1.52, 95% CI 1.40–1.65), lung cancer (HR 1.29, 95% CI 1.04–1.59), agranulocytosis (HR 1.27, 95% CI 1.07–1.51), and lymphatic node metastasis (HR 1.23, 95% CI 1.06–1.43). Twenty-four diseases were associated with multiple organ age gaps or non-corresponding organ gaps. Accelerated organ ageing also predicted increased risk of multiorgan multimorbidity: arterial age gap HR 2.03 (95% CI 1.51–2.74), kidney HR 1.78 (1.48–2.14), heart HR 1.52 (1.38–1.68), brain HR 1.52 (1.12–2.06), pancreas HR 1.43 (1.16–1.78), lung HR 1.37 (1.17–1.61), immune system HR 1.36 (1.26–1.46), and liver HR 1.30 (1.18–1.42).
Why it matters
This study demonstrates that plasma proteomic profiling can quantify organ-specific biological ageing to predict long-term risk of specific diseases and multiorgan multimorbidity up to 20 years in advance.
Limits
The observational design cannot establish causality. The cohort is restricted to UK civil servants, which may limit generalizability to broader populations. Organ age gaps were derived from a single baseline blood measurement without serial updates over time.